The present invention relates to improved pharmaceutical formulations and more specifically relates to constant release rate solid oral dosage formulations of propranolol or a pharmaceutically acceptable salt thereof.
It is an axiom in pharmaceutical science than in order for a drug in an oral solid dosage formulation to be absorbed, it must first become soluble in the aqueous media of the stomach or small intestine. Products which are rapidly dissolved in water are also rapidly absorbed into the body. For such products, controlling their rate of solvation after ingestion also influences their rate of absorption, and drugs which are highly or moderately watersoluble present special formulation problems.
Formulations which effectively control the rate of solvation of highly water soluble drugs are disclosed and claimed in commonly assigned, copending U.S. patent application Ser. No. 443,397, filed Oct. 8, 1982. See also commonly assigned, copending U.S. patent application Ser. No. 364,014 filed Mar. 31, 1982 for constant order release theophylline formulations, allowed U.S. Ser. No. 366,594, filed Apr. 8, 1982 for constant order release aspirin formulations and U.S. Ser. No. 334,124 filed Dec. 24, 1981 for constant release indomethacin formulations. The above commonly assigned, copending application discloses constant order release solid oral dosage formulations which provide a smooth onset of drug action with a subsequent longer duration of pharmacological activity and avoid the peaks and valleys of activity and side effects of drugs administered in conventional formulations, including conventional timed-release formulations. It was also recognized that in view of the number of factors which successfully overcomes the properties peculiar to a specific drug or a group of drugs which share given properties, simply is not suitable for all drugs for the following reasons.
A second factor influencing drug absorption after solubility has occurred is the passage of the drug across the intestinal membrane. A drug generally crosses several membranes to reach its receptor site. This transfer is usually accomplished by passive diffusion. Special transport mechanisms such as facilitated diffusion and active transport allow somes substances to cross cell membranes at a faster rate than simple diffusion. By far, however, the most common mechanism for transport of a drug in solution across the intestinal wall is by passive diffusion.
Passive diffusion is characterized by the movement of the drug molecule down a concentration or electrochemical gradient without the expenditure of cellular energy. The transfer process is neither saturable not inhibited by other materials and is only slightly sensitive to temperature changes. Since most cells in the gastrointestinal tract are in close proximity to capillaries, the passage of drugs across short distances is usually rapid.
The driving force for passive drug transport is the difference between the concentration of the diffusing drug in the intestinal tract and the concentration gradient of the drug on the other side of the plasma membrane. The rate of drug penetration corresponds to the concentration gradient and is characterized by Fick's law.
Many drugs are either an organic acid or a base. Acids donate a hydrogen ion to form a negatively charged anion, while bases accept a hydrogen ion to form a positively charged cation. It is usually assumed that only nonionized, lipid-soluble drugs pass through the lipid rich membranes of the intestinal tract. The ionized molecule is thought to be too polar to penetrate this lipoidal barrier. If it does cross the cell wall, it does so at a slow rate. This concept of drug absorption is known as nonionic diffusion.
An extension of this theory is the pH partition hypothesis, which asserts that the passage rate of a drug through a membrane is dependent upon the pH of the drug's enviroment and the dissociation constant, or "pK.sub.a " of the drug. The pK.sub.a is expressed as the pH at which 50% of the drug will be in the ionized form and 50% will be in the nonionized form. Diffusion of acids and bases across the membrane is not always influenced by pH, as in the case of weak acids or bases. These types of products are essentially completely nonionized at all physiologic pH values. At the other extreme however, are strong acids and bases which are almost completely ionized, and their transfer is dependent upon the pH at which they become dissolved and subsequently becomc ionized or nonionized.
An example of pH partition hypothesis may be explained by the fact that aspirin, which has a pK.sub.a or dissociation constant of between 3 and 3.7 becomes very nonionized in the acid media of the stomach and subsequently is rapidly absorbed from the gastric mucosa, where the pH is between 1 and 3. As the drug particles pass into the small intestines where the pH increases and the rate of ionization is changed so absorption is subsequently slowed. Conversely strong bases such as ephedrine, which has a pK.sub.a of 9.3, or amphetamine with a pK.sub.a of 9.9 are almost negligibly absorbed from the acidic gastric contents, but are absorbed rather rapidly from the intestinal fluid which has a much lower hydrogen ion concentration. By controlling the release of a drug from the tablet matrix one can control the rate of solvation. The rate of absorption for those products having a pK.sub.a above 7 will be greatest, once they reach the small intestine.
While the pH partition hypothesis and nonionic diffusion cannot entirely account for drug absorbtion, however it is one factor to consider among the various factors controlling the rate and mechanism of drug absorbtion in the instestinal tract.
The present invention provides formulations for drugs with a basic nature ie: pk.sub.a 7-10. The formulations of the present invention release their contents in a rather constant manner in the small intestine, thereby controlling the rate at which passive diffusion can occur. While commonly assigned, co-pending U.S. patent application Ser. Nos. 443,497; 364,014; 366,594 and 334,124 disclose various constant release formulations, the present invention provides formulations which take into account the pH partition and which will release basic drugs into the small intestines at a constant and controlled rate, thereby controlling their serum level and prohibiting the peaks and valleys or erratic absorbtion which may be obtained with standard formulations.